Lewis was born and raised in Cincinnati, Ohio to Marlene, a nursing administrator, and Jim Lewis, an air traffic supervisor. She has a sister, Denise. Lewis graduated from Anderson High School there in 1978. She was in a long-term relationship with Nick Nolte. The two met during the filming of I'll Do Anything.

Lewis has had roles in the movies Finding Nemo, Mouse Hunt, Godzilla and Pushing Tin. She was also one of the stars of the short-lived NBC sitcom Three Sisters and the short-lived WB animated comedy Mission Hill. Prior to NewsRadio, she guest-starred as a secretary on both Seinfeld and Murphy Brown. She also played Maureen Binford, producer of Tool Time and one of the Binford girls on Home Improvement. She is well-known in many circles, including theatre and acting. She has a black belt in martial arts. She weighs 131lbs. Lewis' upcoming movie will be along with NewsRadio star Dave Foley in Out Of Omaha.

Lewis' Broadway theatre credits include Do Black Patent Leather Shoes Really Reflect Up?, Damn Yankees, and Chicago. Lewis is often confused with Kathy Griffin, another redhead who concurrently played a similar part to her NewsRadio character on Suddenly Susan. Griffin's character, who perhaps not coincidentally was named Vicki, was once parodied by Lewis on a NewsRadio episode by straining her voice very deeply. Lewis has been vocal about the debacle on NewsRadio DVD audio commentaries.